Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

HDAC1/2 are required for microglia identity during development, homeostasis and neurodegeneration in a context-dependent manner [ChIP inducible knockout on FAD background]

ABSTRACT: Microglia as tissue macrophages of the central nervous system (CNS) provide immunological defense and contribute to the establishment and maintenance of CNS homeostasis. Several transcription factors have been described that regulate microglia development and its steady state form, however little is known about the epigenetic signals that control microglia function in vivo. Here, we employed constitutive and inducible mutagenesis in microglia to delete two class I histone deacetylases (HDACs), Hdac1 and 2. Prenatal ablation of Hdac1 and 2 from microglia drastically impaired microglial development with reduced cell number, altered morphology and induction of apoptosis. Comparative transcriptomic profiling revealed an essential role of Hdac1/2 in the regulation of microglia survival and expansion. Mechanistically, hyperacetylation at H3K9 and H3K27 was found at the promoters of pro-apoptotic and cell cycle genes in the absence of Hdac1/2. In contrast, Hdac1/2 were not required in adult microglia during homeostasis. In a mouse model of Alzheimer’s disease, suppression of Hdac1/2 in microglia, but not in neuroectodermal cells, remarkably displayed substantial decrease in amyloid load and improved cognitive impairment by enhancing microglial amyloid phagocytosis. Collectively, we report a previously unknown role of epigenetic factors that differentially affect microglia development, homeostasis and disease that could potentially be utilized therapeutically.

ORGANISM(S): Mus musculus

PROVIDER: GSE110166 | GEO | 2018/03/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

HDAC1/2 are required for microglia identity during development, homeostasis and neurodegeneration in a context-dependent manner [ChIP-seq constitutive knockout]

Project description:Microglia as tissue macrophages of the central nervous system (CNS) provide immunological defense and contribute to the establishment and maintenance of CNS homeostasis. Several transcription factors have been described that regulate microglia development and its steady state form, however little is known about the epigenetic signals that control microglia function in vivo. Here, we employed constitutive and inducible mutagenesis in microglia to delete two class I histone deacetylases (HDACs), Hdac1 and 2. Prenatal ablation of Hdac1 and 2 from microglia drastically impaired microglial development with reduced cell number, altered morphology and induction of apoptosis. Comparative transcriptomic profiling revealed an essential role of Hdac1/2 in the regulation of microglia survival and expansion. Mechanistically, hyperacetylation at H3K9 and H3K27 was found at the promoters of pro-apoptotic and cell cycle genes in the absence of Hdac1/2. In contrast, Hdac1/2 were not required in adult microglia during homeostasis. In a mouse model of Alzheimer’s disease, suppression of Hdac1/2 in microglia, but not in neuroectodermal cells, remarkably displayed substantial decrease in amyloid load and improved cognitive impairment by enhancing microglial amyloid phagocytosis. Collectively, we report a previously unknown role of epigenetic factors that differentially affect microglia development, homeostasis and disease that could potentially be utilized therapeutically.

2018-03-14 | GSE107436 | GEO

Expression data from Hdac1 and 2 knock out microglia in 5X familial Alzheimer's disease (FAD) background

Project description:Epigenetic alterations has been implicated in the pathology of several neurodegenerative diseases. To investigate the role of microglial Hdac1 and 2 in the pathogenesis of Alzheimer's disease (AD), we created microglia specific compound Hdac1 and Hdac2 knock out mice in 5X FAD background. Genetic ablation of Hdac1 and 2 from microglia reduced amyloid plaque burden and improved spatial learning and memory function. To study how Hdac1 and 2 knock out in microglia alters gene expression profile in 5X FAD mice we carry out microarray analysis using 24-28 weeks animals

2018-03-14 | GSE96622 | GEO

Bulk RNA-seq of FACS sorted astrocytes upon microglial depletion

Project description:As the professional phagocyte in the central nervous system (CNS), microglia are the primary scavenger removing cell corpses. The failure of microglia in debris clearance influences the normal CNS function. Meanwhile, microglia undergo turnover during the whole lifespan. If dead microglia are not timely removed, accumulated corpses may influence the CNS function. The microglial corpse clearance is hereby crucial for CNS homeostasis. However, the underlying mechanism remains obscure. In this study, we investigated how microglial corpses are removed. We found that microglial corpses are mainly phagocytosed by astrocytes, mediated by C4b opsonization. Then engulfed microglial fragments are degraded in astrocytes via the RUBICON-dependent LC3-associated phagocytosis (LAP), a form of non-canonical autophagy. The interference of the C4b-mediated engulfment and its subsequent LAP disrupt the microglial debris removal and degradation, respectively. Together, we elucidated cellular and molecular mechanisms of microglial debris removal, extending the knowledge on how the CNS homeostasis is maintained.

2022-09-01 | GSE171321 | GEO

Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation

Project description:Microglia are necessary for CNS function during development and play roles in aging, Alzheimer’s Disease (AD) and the response to demyelinating injury. Mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation6 and macrophage-dependent immune responses. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Rieske Iron-Sulfur Protein (RISP) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation, and adult CNS function in vivo. Surprisingly, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA-seq analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia (DAM). Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-β plaque coverage decreased and microglial interaction with Amyloid-β plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.

2024-06-10 | GSE269239 | GEO

Microarray analysis to evaluate the function of USP18 in the mouse CNS

Project description:Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called ‚Äòmicrogliopathies‚Äô. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulated the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signalling. Unexpectedly, the Usp18-mediated feedback loop was independent from the catalytic domain of the protease but instead required the interacting region of Ifnar2. Additionally, the absence of Ifnar1 completely rescued microglial activation indicating a tonic IFN signal mediated by receptor interactions under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal and myelin damage and determined the spatial distributions of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as novel negative regulator of microglia activation, demonstrate a protective role of the IFNAR pathway for microglia and establish Usp18 as potential therapeutic target for the treatment of MS. Brain lysate of adult WT, USP18ko, IFNAR1ko and USP18ko:IFNARko mice were analyzed

2015-04-20 | E-GEOD-61499 | biostudies-arrayexpress

Microarray analysis to evaluate the role of USP18 in primary microglia and the microglia cell line BV-2

Project description:Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called ‘microgliopathies’. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulated the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signalling. Unexpectedly, the Usp18-mediated feedback loop was independent from the catalytic domain of the protease but instead required the interacting region of Ifnar2. Additionally, the absence of Ifnar1 completely rescued microglial activation indicating a tonic IFN signal mediated by receptor interactions under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal and myelin damage and determined the spatial distributions of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as novel negative regulator of microglia activation, demonstrate a protective role of the IFNAR pathway for microglia and establish Usp18 as potential therapeutic target for the treatment of MS. Primary microglia (WT, USP18ko and USP18_C61A mice) and BV-2 cells (treated with control siRNA or siRNA against USP18) were incubated with 500 U/ml IFN-b. At different timepoints (0h, 6h, and 24h) RNA samples were taken and analyzed via Microarray

2015-04-20 | E-GEOD-61500 | biostudies-arrayexpress

IL-10 prevents pathological microglia hyperactivation following peripheral endotoxin challenge

Project description:Microglia, the resident macrophages of the brain parenchyma, are central players in CNS development, homeostasis and disorders. Distinct brain pathologies seem associated with discrete microglia activation modules. How microglia regain their ground state following challenges remains much less understood. Here, we explored the role of the IL-10 axis in restoring murine microglia homeostasis following peripheral endotoxin challenge. Specifically, we show that lipopolysaccharide (LPS)-challenged mice harboring IL-10 receptor-deficient microglia display neuronal impairment and succumb to fatal sickness. Addition of a microglial TNF deficiency rescues these animals, suggesting a microglia-based circuit driving pathology. Single cell transcriptome analysis revealed various IL-10 producing resident and recruited immune cell in the CNS, including most prominently Ly49D+ NK cells and neutrophils, but not microglia. Collectively, we define the kinetics of the microglia response to peripheral endotoxin challenge, including their activation and robust silencing, and highlight the critical role of non-microglial IL-10 in preventing deleterious microglia hyperactivation.

2020-10-22 | GSE157480 | GEO

Identification of a Unique TGF-β Dependent Molecular and Functional Signature in Microglia

Project description:Microglia are myeloid cells of the central nervous system (CNS) that participate both in normal CNS function and disease. We investigated the molecular signature of microglia and identified 239 genes and 8 microRNAs that were uniquely or highly expressed in microglia vs. myeloid and other immune cells. Out of 239 genes, 106 were enriched in microglia as compared to astrocytes, oligodendrocytes and neurons. This microglia signature was not observed in microglial lines or in monocytes recruited to the CNS and was also observed in human microglia. Based on this signature, we found a crucial role for TGF-β in microglial biology that included: 1) the requirement of TGF-β for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia; and 2) the absence of microglia in CNS TGF-β1 deficient mice. Our results identify a unique microglial signature that is dependent on TGF-β signaling which provides insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease.

2013-07-08 | GSE48579 | GEO

Distinct amyloid-b and tau associated microglia profiles in Alzheimer's disease

Project description:Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-b and intraneuronal hyperphosphorylated, tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-b and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-b plaques or both amyloid-b plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-b load and localized to amyloid-b plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with over tau pathology. This full characterization of human disease associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.

2021-02-20 | GSE148822 | GEO

Microglia-derived TGF-β1 ligand maintains microglia homeostasis via autocrine mechanism and is critical for normal cognitive function in adult mouse brain

Project description:While TGF-β signaling is essential for microglial function, the cellular source of TGF-β ligand and its spatial regulation remains unclear in adult CNS. Our data supports that microglia but not astrocytes or neurons are the primary producers of TGF-β1 ligands needed for microglial homeostasis. Microglia-Tgfb1 KO leads to activation of microglia featuring a dyshomeostatic transcriptomic profile that resembles disease-associated microglia (DAMs), injury-associated microglia, and aged microglia, suggesting that microglial self-produced TGF-β1 ligands are important in the adult CNS. Interestingly, astrocytes in the MG-tgfb1 iKO mice show a transcriptome profile that is closely aligned with A1-like astrocytes. Additionally, using sparse mosaic single cell microglia KO of TGF-β1 ligand we established an autocrine mechanism for TGF-β signaling. Importantly MG-Tgfb1 inducible KO mice show cognitive deficits, supporting that precise spatial regulation of TGF-β1 ligand derived from microglia is critical for the maintenance of brain homeostasis and normal cognitive function in the adult brain.

2023-08-08 | GSE236032 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data